Homeotic Arm-to-Leg Transformation Associated with Genomic Rearrangements at the PITX1 Locus

• Published in: American journal of human genetics Vol. 91; no. 4; pp. 629 - 635
• Main Authors: SPIELMANN, Malte, BRANCATI, Francesco, FERRARI, Paola, LANDI, Antonio, WITTLER, Lars, TIMMERMANN, Bernd, CHAN, Danny, MENNEN, Ulrich, KLOPOCKI, Eva, MUNDLOS, Stefan, KRAWITZ, Peter M, ROBINSON, Peter N, IBRAHIM, Daniel M, FRANKE, Martin, HECHT, Jochen, LOHAN, Silke, DATHE, Katarina, NARDONE, Anna Maria
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Cell Press 05-10-2012; Elsevier
• Subjects: Animals; Biological and medical sciences; Brachydactyly - genetics; Carpal Bones - abnormalities; Comparative Genomic Hybridization - methods; Developmental biology; Elbow Joint - abnormalities; Female; Fingers - abnormalities; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Expression Regulation, Developmental; Gene Rearrangement; Genes, Homeobox; Genetic Loci; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomics; Genotype & phenotype; Hand Deformities, Congenital - genetics; Humans; Legs; Male; Medical disorders; Medical genetics; Medical sciences; Mice; Mice, Transgenic; Molecular and cellular biology; Morphology; Mutation; Paired Box Transcription Factors - genetics; Sequence Analysis, DNA - methods; Synostosis - genetics; Transformation, Genetic; Translocation, Genetic; Wrist Joint - abnormalities; Genetics; Transformation; Locus; Arm; Leg
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.08.014

The study of homeotic-transformation mutants in model organisms such as Drosophila revolutionized the field of developmental biology, but how these mutants relate to human developmental defects remains to be elucidated. Here, we show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation, shows features of a homeotic limb transformation in which the arms have acquired morphological characteristics of a leg. Using high-resolution array comparative genomic hybridization and paired-end whole-genome sequencing, we identified two deletions and a translocation 5' of PITX1. The structural changes are likely to remove active PITX1 forelimb suppressor and/or insulator elements and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. We generated transgenic mice in which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype.